Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF

疟原虫 MIF 对适应性免疫的炎症抑制

• 批准号: 8822823
• 负责人: RICHARD J BUCALA
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822823
• 关键词: Accounting; Antigens; Antimalarials; Apoptosis; Binding; Binding Proteins; Biological Models; Blood; Brugia; CD4 Positive T Lymphocytes; CD44 gene; Cells; Cessation of life; Communicable Diseases; Cytokine Signaling; Data; Development; Environment; Erythrocytes; Evaluation; Foundations; Generations; Genes; Genomics; Goals; Health; Helper-Inducer T-Lymphocyte; Hookworms; Human; Immune response; Immunity; Immunization; Infection; Inflammatory; Inflammatory Response; Investigation; Knowledge; Lead; Leishmania; Malaria; Malaria Vaccines; Mediating; Memory; Migration Inhibitory Factor; Molecular; Mus; N-terminal; Orthologous Gene; Parasitemia; Parasites; Pathway interactions; Plasmodium; Production; Property; Proteins; RNA; Receptor Activation; Research; Role; Signal Pathway; Signal Transduction; Sporozoites; Staging; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Therapeutic; Toll-like receptors; Transducers; Vaccine Therapy; Vaccines; Work; adaptive immunity; base; cytokine; design; exhaustion; experience; filaria; immunoregulation; inhibitor/antagonist; insight; memory CD4 T lymphocyte; mouse model; novel; novel therapeutic intervention; pathogen; phenylpyruvate tautomerase; receptor; response; small molecule; transmission process; vaccine development

DESCRIPTION (provided by applicant): The inability to acquire fully protective immunity against Plasmodium is a chief obstacle to malaria control. High levels of inflammatory cytokines can inhibit memory T cell development in model systems. Notably, all Plasmodia species have been found to encode an ortholog of the upstream inflammatory cytokine, macrophage migration inhibitory factor (MIF). Plasmodium MIF (PMIF) upregulates inflammatory responses during infection, leading to enhanced activation-induced T cell apoptosis and fewer antigen- experienced CD4 T cells that become memory cells. This finding suggests that Plasmodia actively interfere with the generation of malaria-specific memory CD4 T cells to enable parasite persistence and transmission. To better understand ineffective immunity to malaria and to provide a foundation for better vaccines, we will determine the specific role of PMIF in the anti-malarial immune response in three Specific Aims, as follow: Aim 1. Define the Molecular Basis for the Pro-inflammatory Activation of the Immune Response by Plasmodium-encoded MIF (PMIF). We hypothesize that PMIF increases inflammatory responses by activating the host MIF receptor. We will define shared and unique signaling properties of PMIF versus host MIF and examine the role of the conserved N-terminal region, which mediates binding to the MIF receptor. We will investigate the action of PMIF on Toll-like and NOD-like receptor activation pathways, and we will validate our observations in mice infected with a P. berghei ANKA strain lacking its mif gene. Aim 2. Define the Cellular and Molecular Basis for the Suppression of the Anti-malarial Adaptive Immune Response by PMIF. We hypothesize that a strong pro-inflammatory environment during malaria infection favors the generation of terminal effector CD4 T cells at the expense of protective, memory precursor CD4 T cells. We will elucidate the cytokine and signaling pathways responsible for this response, examine the role of T follicular helper cells (TFH) and their ability to provide help to B and to T cells, and analyze T cell exhaustion. Aim 3. Evaluate the Therapeutic Potential of PMIF Neutralization in Malaria. We will explore the impact of neutralization of PMIF in mouse models of blood-stage and sporozoite infection. Our approach will include immunization with PMIF by a novel self-amplifying RNA vaccine and a pharmacologic strategy based on our discovery of a selective, small molecule inhibitor of PMIF. These studies will provide insight into how Plasmodia direct the host inflammatory response to interfere with protective immunity and suggest new strategies for therapeutic immunomodulation and vaccine development. Conclusions from this work may be generalized to other parasite pathogens, such as Leishmania, Ancyclostoma, and Brugia, which produce their own closely homologous MIF proteins.

描述（由申请人提供）：无法获得对疟原虫的完全保护性免疫是控制疟疾的主要障碍。在模型系统中，高水平的炎症细胞因子可以抑制记忆T细胞的发育。值得注意的是，所有疟原虫都编码上游炎症细胞因子巨噬细胞迁移抑制因子（MIF）的同源物。疟原虫MIF （PMIF）在感染过程中上调炎症反应，导致激活诱导的T细胞凋亡增强，抗原经历的CD4 T细胞成为记忆细胞减少。这一发现表明，疟原虫积极地干扰疟疾特异性记忆CD4 T细胞的产生，使寄生虫能够持续存在和传播。为了更好地了解对疟疾的无效免疫，并为研制更好的疫苗奠定基础，我们将在以下三个具体目标中确定PMIF在抗疟疾免疫反应中的具体作用：目标1。通过疟原虫编码的MIF （PMIF）确定免疫反应的促炎激活的分子基础。我们假设PMIF通过激活宿主MIF受体来增加炎症反应。我们将定义PMIF与宿主MIF的共享和独特的信号特性，并检查保守n端区域的作用，该区域介导与MIF受体的结合。我们将研究PMIF对toll样和nod样受体激活途径的作用，并将在感染缺乏mif基因的伯格氏假体ANKA菌株的小鼠中验证我们的观察结果。目标2。确定PMIF抑制抗疟疾适应性免疫反应的细胞和分子基础。我们假设，在疟疾感染期间，强烈的促炎环境有利于产生终末效应CD4 T细胞，而牺牲了保护性的记忆前体CD4 T细胞。我们将阐明负责这种反应的细胞因子和信号通路，检查T滤泡辅助细胞（TFH）的作用及其向B细胞和T细胞提供帮助的能力，并分析T细胞衰竭。目标3。评价PMIF中和治疗疟疾的潜力。我们将探讨中和PMIF对血期和孢子虫感染小鼠模型的影响。我们的方法将包括通过一种新的自我扩增RNA疫苗对PMIF进行免疫接种，以及基于我们发现的PMIF选择性小分子抑制剂的药理学策略。这些研究将深入了解疟原虫如何指导宿主炎症反应，干扰保护性免疫，并为治疗性免疫调节和疫苗开发提供新的策略。这项工作的结论可以推广到其他寄生虫病原体，如利什曼原虫、钩虫和布鲁吉亚原虫，它们产生自己的密切同源的MIF蛋白。